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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

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2.2 Dimethyl sulfoxide (DMSO)

2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to dimethyl sulfoxide as follows:

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Schedule 6 - Amend Entry

DIMETHYL SULFOXIDE (excluding dimethyl sulfone):

  1. when not for therapeutic use; or
  2. in cosmetic preparations; or
  3. for the treatment of animals:
    1. when combined with no other therapeutic substance(s);
    2. in liquid preparations containing copper salicylate and 1 per cent or less of methyl salicylate as the only other therapeutic substances; or
    3. in clay poultices containing 2 per cent or less of dimethyl sulfoxide; or
  4. in other preparations except when containing 10 per cent or less of dimethyl sulfoxide.

Schedule 4 - Amend Entry

DIMETHYL SULFOXIDE (excluding dimethyl sulfone) in preparations for therapeutic use except:

  1. when included in Schedule 6; or
  2. in in vitro test kits; or
  3. when used as a flavour component when the total flavour content is 5 per cent or less of the preparation.

Proposed implementation date: 1 February 2019

Reasons

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Risks:
      • DMSO is a carrier/universal solvent that enhances skin penetration of other substances and thus renders internal organs permeable to drugs and chemicals, leading to enhanced therapeutic and/or toxic responses.
      • DMSO is an eye and skin irritant in undiluted form.
    • Benefits:
      • DMSO has a number of therapeutic uses due to its low toxicity.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • DMSO is used as a commercial solvent.
    • DMSO is found in a number of human therapeutic preparations, including for dermal use, at concentrations greater than 10%.
    • Only non-therapeutic uses of DMSO are covered by the proposed exemption.
    • DMSO is prohibited in cosmetic products in the EU (Regulation (EC) No 1223/2009 - Annex II).
  3. the toxicity of a substance:
    • DMSO is of low acute toxicity but is considered both a skin and eye irritant at concentrated doses. It is a mild irritant to both skin and eyes.
    • Toxicity of dilute DMSO preparations is low (at most, slight skin and eye irritation only).
    • DMSO enhanced dermal penetration of other compounds and may thereby enhance toxicity of these compounds.
    • DMSO is not expected to be genotoxic, carcinogenic, nor to have reproductive or developmental toxicity.
    • Long-term oral or dermal administration produces only slight toxicity. The proposed exposure to DMSO is not a health concern.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Schedule 6 products require labelling and packaging in accordance with the Poisons Standard. Labelling of unscheduled products is the responsibility of the manufacturer / supplier.
    • The acute toxicity data supports a cut-off for DMSO in Schedule 6. Although the toxicity data presented by the applicant corresponds to DMSO concentrations of 60% and greater, 10% is a conservative and therefore reasonable estimate to ensure no significant toxicity in exempt preparations.
  5. the potential for abuse of a substance:
    • Scheduling history reports abuse in the 1980s but no recent reports and risk appears low.
  6. any other matters that the Secretary considers necessary to protect public health:
    • The intention of the Schedule 4 amendment is to align this entry with the requirements of the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2018.

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to dimethyl sulfoxide;
  • The advice received from the Joint Advisory Committees on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19);
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for dimethyl sulfoxide

Delegate's referral to ACCS/ACMS

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to dimethyl sulfoxide (DMSO). The application proposed to amend the Schedule 6 entry for in the Poisons Standard by introducing a new exemption concentration cut-off.

Applicant's scheduling proposal and reasons

The application proposed the following amendments to the Poisons Standard:

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Deleted text is shown as red, smaller font, with a strikethrough.

Schedule 6 - Amend Entry

DIMETHYL SULFOXIDE (excluding dimethyl sulfone):

  1. when in preparations not for therapeutic use and containing 10 per cent or less of dimethyl sulfoxide; or
  2. for the treatment of animals:
    1. when combined with no other therapeutic substance(s);
    2. in liquid preparations containing copper salicylate and 1 per cent or less of methyl salicylate as the only other therapeutic substances; or
    3. in clay poultices containing 2 per cent or less of dimethyl sulfoxide.

The applicant's reasons for the proposal were:

  • DMSO was found to have low acute oral, dermal and inhalational toxicity. DMSO is a non-skin sensitiser but is a slight skin and eye irritant at high concentrations. Repeat dose toxicity studies performed by oral, dermal, and inhalational routes revealed no toxicity at a limit dose (1000 mg/kg/day). DMSO is also non-carcinogenic, non-genotoxic and has a low potential for any reproductive or developmental toxicity.
  • The potential for slight acute skin and eye irritation appears to be concentration dependent but only at levels in excess of 66%, primarily due to the heat generated when DMSO comes into contact with water (a potent exothermic reaction).
  • At low concentrations (approximately 10% and less), DMSO is not expected to induce skin or eye irritation in humans.
  • DMSO is currently in use in a number of human therapeutic preparations, including dermal topical formulations, at concentrations greater than 10%.

Current scheduling status

DMSO is listed in Schedules 4 and 6, and Appendices E and F of the Poisons Standard as follows:

Schedule 4

DIMETHYL SULFOXIDE (excluding dimethyl sulfone) for therapeutic use except:

  1. when included in Schedule 6; or
  2. in in vitro test kits.

Schedule 6

DIMETHYL SULFOXIDE (excluding dimethyl sulfone):

  1. when not for therapeutic use; or
  2. for the treatment of animals:
    1. when combined with no other therapeutic substance(s);
    2. in liquid preparations containing copper salicylate and 1 per cent or less of methyl salicylate as the only other therapeutic substances; or
    3. in clay poultices containing 2 per cent or less of dimethyl sulfoxide.

Appendix E, Part 2

DIMETHYL SULFOXIDE

Standard Statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), G3 (If swallowed, do NOT induce vomiting), E1 (If in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water)

Appendix F, Part 3

DIMETHYL SULFOXIDE Warning Statement Safety Direction
  1. when not packed and labelled for therapeutic use.
27 (Not for therapeutic use) 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 5 (Wear protective gloves when mixing or using), 8 (Avoid breathing dust (or) vapour (or) spray mist)
  1. when packed and labelled for the treatment of animals.
49 (WARNING - Do not mix with other medication except on veterinarian's advice) 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 5 (Wear protective gloves when mixing or using), 8 (Avoid breathing dust (or) vapour (or) spray mist)

Index

DIMETHYL SULFOXIDE
cross reference: COPPER SALICYLATE, METHYL SALICYLATE

Schedule 6
Schedule 4
Appendix E, Part 2
Appendix F, Part 3

Scheduling history

DMSO has a long and thorough scheduling history dating back to 1965, whereby all uses have been considered. DMSO was first listed in Schedule 6 (Poison) of the Poisons Standard in 1965 based on toxicological concerns including potentially causing eye lens opacities. This entry included the warning statement in the label 'avoid contact with the skin and avoid breathing its vapour'. It was subsequently listed in Schedule 4 (Prescription Only Medicine) for therapeutic use based on concerns to regulate high-dose human therapeutic use (including clinical trials) for a variety of arthritic conditions. However, DMSO was only to be used with approval of the Commonwealth Director-General of Health.

During the 1980s - 1990s, the Schedule 6 entry was amended to enable some dermally applied veterinary products to escape Schedule 4 controls. The principal concern of DMSO and the reasons for scheduling was to alert those applying the medications to the known propensity for DMSO to markedly enhance the skin penetration of other substances and its capacity to render other organs permeable to drugs and chemicals. This could lead to an enhanced therapeutic response via more extensive absorption of any active therapeutic substances in the preparations. Due to this property, any DMSO-containing formulation should be treated as a new drug. It was also for this reason that the Schedule 6 amendments specified that it only applies when there no other therapeutically active substance in the formulation, or it is a specific formulation that has been assessed as suitable for a Schedule 6 listing. There were also reports of DMSO being abused or prescribed illegally. The Schedule 6 listing also provides for an Appendix F Warning Statement relating to the potential for enhanced skin absorption of other active substances.

Australian regulations

DMSO is permitted for use as an excipient in biologicals, devices, listed medicines and prescription medicines; and as an active ingredient in biologicals and prescription medicines. Restrictions apply to its use in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirement(s) applying to the ingredient in Column 2

1829 DIMETHYL SULFOXIDE E

Permitted for use only in combination with other permitted ingredients as a flavour.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

There are 33 products (31 biologicals and 2 medical devices) on the Australian Register of Therapeutic Goods (ARTG) that contain DMSO at concentrations up to 27%.

DMSO (methane, sulfinylbis-) is listed on the Australian Inventory of Chemical Substances (AICS) and a Human Health Tier II Assessment for Methane, sulfinylbis- has been completed by NICNAS.

Agricultural and veterinary chemicals containing DMSO are listed on the APVMA's PubCRIS. Currently, DMSO is present in some agricultural chemicals at concentrations of up to 515 g/L, and in veterinary chemical preparations of up to 900 mg/g.

International regulations

European Union

DMSO has been considered by the European Chemicals Agency (ECHA) as part of the REACH program.

One orphan designation has been granted by the European Commission for DMSO for the treatment of severe closed traumatic brain injury.

United States (US)

DMSO is a prescription medicine in the US and can be used in concentrations up to 50% in medicines for human use. In animals, DMSO is approved for use only in horses and dogs.

Canada

There are 9 prescription medicines that contain DMSO as an active ingredient in Canada, only 3 of which (1 human medicine and 2 veterinary medicines) are currently marketed. Concentrations of DMSO used in the medicines range from 50% (human medicines) to 90% (veterinary medicines).

Substance summary

Table 2.2A: Chemical information for dimethyl sulfoxide
Property Dimethyl sulfoxide
CAS number 67-68-5
IUPAC and/or common and/or other names Dimethyl sulfoxide (IUPAC); sulfinylbismethane (CAS)
Chemical structure Chemical structure of DMSO
Molecular formula C2H6OS
Molecular weight 78.1 g/mol
Table 2.2B: Acute toxicity end-points for dimethyl sulfoxide
Toxicity Species Dimethyl sulfoxide SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg) Rat 28300 mg/kg -
Acute dermal toxicity LD50 (mg/kg) Rat 40000 mg/kg -
Acute inhalational toxicity LC50 (mg/m3/4h) Rat (4h) >5330 mg/m3 -
Skin irritation Rabbit Slight skin irritant when applied undiluted 6
Eye irritation Rabbit Slight eye irritant when instilled undiluted 6
Skin sensitisation Mouse (LLNA) Non-sensitiser -
Acute toxicity

DMSO has low acute oral, dermal and inhalational toxicity.

Skin irritation

When applied undiluted (>66%), DMSO is a skin irritant.

When applied in diluted form (<66%), DMSO is a slight skin irritant.

Dermal exposure to DMSO causes skin reactions, erythema and pruritus, which are seen immediately after contact with the undiluted substance. Solutions of 70% are generally well tolerated in humans without symptoms. The skin reaction to the undiluted substance is considered to be the result of the exothermic reaction (heat releasing) process of DMSO when mixed with water. DMSO, being very hygroscopic readily draws water from the atmosphere (and surrounding dermal or ocular tissues).

In a controlled study, 1 g of gel containing 80% DMSO was applied to the skin of 78 human subjects daily for 2 weeks. In addition to the skin reactions noted above, sedation developed in 52%, headaches in 42%, sleepiness in 18% and nausea in 32% of subjects. Moreover, there were no changes noted in the eyes of the subjects.

Eye irritation

When instilled undiluted (>66%), DMSO is an eye irritant.

When instilled in diluted form (<66%), DMSO is a slight eye irritant.

Sensitisation

DMSO is not considered to be a skin sensitiser.

Repeat-dose toxicity

The main effects of very high doses of DMSO administered to experimental animals by intravenous injection are morphological and functional changes in the liver and kidney. Long-term oral or dermal administration produces only slight toxicity. Hepatotoxicity and nephrotoxicity have not been described in humans (MAK, 1992).

Genotoxicity

DMSO is not considered to be genotoxic.

Carcinogenicity

Based on the limited data available, DMSO is not expected to be carcinogenic.

Reproduction and developmental toxicity

Based on the available data, DMSO is not considered to have reproductive or developmental toxicity.

Observation in humans

Observations in humans after repeated dermal exposure indicate that DMSO can cause skin dryness or cracking due to its defatting (dissolving dermal lipids) and drying characteristics. Exposure to undiluted (>66%) preparations of DMSO are associated with eye and skin irritation. There are no other critical health effects expected from exposure to diluted preparations of the chemical.

Pre-meeting public submissions

No public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations.

Joint ACMS-ACCS advice

The committee recommended that the current Schedule 6 entry for dimethyl sulfoxide be amended as follows:

Note

New text is shown as green, larger font, with a horizontal line above it.

Schedule 6 - Amend Entry

DIMETHYL SULFOXIDE (excluding dimethyl sulfone):

  1. in cosmetic preparations; or
  2. for the treatment of animals:
    1. when combined with no other therapeutic substance(s);
    2. in liquid preparations containing copper salicylate and 1 per cent or less of methyl salicylate as the only other therapeutic substances; or
    3. in clay poultices containing 2 per cent or less of dimethyl sulfoxide; or
  3. in other preparations except when containing 10 per cent or less of dimethyl sulfoxide.

The committee also recommended that the current Schedule 4 entry for dimethyl sulfoxide be amended to align this entry with the requirements of the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, which specifies that in listed medicines, dimethyl sulfoxide is permitted for use only in combination with other permitted ingredients as a flavour and if used in a flavour, the total flavour concentration in a medicine must be no more than 5%. The amendments suggested for the Schedule 4 dimethyl sulfoxide entry are as follows:

Schedule 4 - Current Entry

DIMETHYL SULFOXIDE (excluding dimethyl sulfone) in preparations for therapeutic use except:

  1. when included in Schedule 6; or
  2. in in vitro test kits; or
  3. when used as a flavour component when the total flavour content is 5 per cent or less of the preparation.

The committee also recommended an implementation date of 1 February 2019.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

  1. risks and benefits of the use of a substance:
    • Combinations of DMSO with other toxic substances account for most of DMSO's toxic potential.
    • DMSO is an eye and skin irritant in undiluted form.
    • DMSO has a number of therapeutic uses due to its low toxicity.
  2. the purpose for which a substance is to be used and the extent of use:
    • DMSO is used for both therapeutic purposes and as a commercial solvent.
    • Only non-therapeutic uses of DMSO are covered by the proposed exemption.
  3. the toxicity of a substance:
    • DMSO is of low acute toxicity but is considered both a skin and eye irritant at concentrated doses. It is a mild irritant to both skin and eyes.
    • Toxicity of dilute DMSO preparations is low (at most, slight skin and eye irritation only).
    • DMSO enhances dermal penetration of other compounds and may thereby enhance toxicity of these compounds.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Schedule 6 products require labelling and packaging in accordance with the Poisons Standard. Labelling of unscheduled products is the responsibility of the manufacturer / supplier.
  5. the potential for abuse of a substance:
    • Scheduling history reports abuse in the 1980s but no recent reports and risk appears low.
  6. any other matters that the Secretary considers necessary to protect public health:
    • The intention of the committee advice regarding amendments to the Schedule 4 entry is to align this entry with the requirements of the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018.

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